The regulation of intracellular pH (pHi) and extracellular pH (pHo) of brain is critical for optimizing neuronal excitability. Na-Coupled Bicarbonate Transporters (NCBTs) ?particularly the astrocytic electrogenic Na/bicarbonate cotransporter NBCe1 that couples changes in pH with neuronal activity? are key regulators of brain pH. Despite the clear importance of pH regulation and the abundance of NBCe1 in brain, the role of NBCe1 and associated pH changes in modulating synaptic transmission and synaptic plasticity has not be identified. The current objective is to use molecular and pharmacological tools with electrophysiological approaches in brain-slice studies to investigate the role of NBCe1 and associated pH changes in modulating hippocampal synaptic function. Aim 1 is to address the hypothesis that NBCe1 dampens basal, low-frequency synaptic transmission. A combination of extracellular and whole-cell recordings in CA1 of acute hippocampal slices from wild-type and NBCe1 knockout (KO) mice will be used to investigate the role of NBCe1 in regulating synaptic transmission and spiking in hippocampal CA1 in response to low-frequency (0.1 Hz) extracellular stimulation. The effects of NBCe1 inhibitors (S0859 and a function blocking L3 antibody), a function stimulating L4 antibody, and viral restoration of NBCe1 into astrocytes in NBCe1 KO mice will be determined. pH-sensitive microelectrodes and dyes will be used to examine associated changes in pHo, as well as the pH of astrocytes and presynaptic terminals to test the hypothesis that inhibiting NBCe1 stimulates basal synaptic transmission by enhancing the extracellular alkaline shift (established conventional model). Aim 2 is to address the hypothesis that NBCe1 enhances high-frequency synaptic transmission and long-term plasticity. The molecular and pharmacological tools and approaches described for Aim 1 will be used to examine excitatory synaptic responses, but in response to high-frequency (50 Hz) extracellular stimulation. pH measurements will be made in the extracellular space, astrocytes, and presynaptic nerve terminals to test the hypothesis that NBCe1 stimulation of high-frequency synaptic transmission and long-term potentiation (LTP) involves dampening of the activity-evoked presynaptic pHi decrease (new mechanism). Underlying mechanisms such as pre- vs postsynaptic responses and the role of specific receptors will be evaluated for both Aims. Results will reveal that NBCe1 is a physiologically important acid-base transporter that modulates synaptic transmission and LTP through changes in pH that are dependent on frequency stimulation. The results will contribute to our understanding of NBCe1 and associated pH changes in neuronal activity, seizures, ischemia, and hypoxia.